Gower sign
positive muscle weakness in a patient with short stature and hypophosphatemia

Omyma Sabir*,
Abdelaziz Elamin*, Mohamed Elabyad*

Abstract

A 17-year-old
Sudanese patient presented with short stature, generalized body aches, and
proximal muscle weakness. He was seen by two orthopedic surgeons and an adult
neurologist and misdiagnosed as having benign bone cysts, osteomalacia and
Duchenne muscular dystrophy. In fact, he was suffering from severe
hypophosphatemia, which manifest by unusual presentation. The diagnostic
pitfalls are explained and the importance of urinalysis and measurement of bone
minerals are emphasized.

Keywords: Renal
tubular acidosis, Fanconi syndrome, Rickets.

Phosphorus is an
inorganic anion. Most of the phosphorus in the human body is in the bone and
the intracellular compartment. The plasma concentration of phosphorus is age
dependent and does not reflect the total body stores because only 1% of
phosphorus is found in the extracellular compartment. Children have higher
concentrations of plasma phosphorus compared to adults because they have
greater need for phosphorus to facilitate physical growth. Phosphorus as a
component of ATP and other tri-nucleotides is critical for cellular energy metabolism.
It is necessary for nucleic acid synthesis, and for formation of
phospho-lipids, which is part of cell membranes and other structures. Along
with calcium, phosphorus is an essential component of bone, and it is necessary
for proper mineralization 1-4. Through it is synergistic and
reciprocal integration with calcium, phosphorus affects the action potential of
skeletal muscles and its contractions. Hypophosphatemia is caused by tubular
renal defects, hyperparathyroidism and nutritional factors 5-9. When
severe it manifest as rickets with hypotonia and muscle weakness 10-11.
Below we describe in details the clinical problem of a young patient with
hypophosphatemia, who was misdiagnosed and under treated
because of unusual presentation.

Case History:

A previously
healthy 17-year-old adolescent boy from Northern Sudan presented with
difficulty in standing from sitting position for one year prior to admission,
to Gaffer Ibn Auf Children Teaching Hospital in Khartoum. This condition was
not associated with muscle or joint pain, morning stiffness, fever or skin
rash. No post-exertional cramps or exercise intolerance. No symptoms related to
the central or peripheral nervous system. It was not preceded by trauma and not
affecting his walking so he did not seek medical advice at that time. Two
months later he developed pain in his right ankle, moderate in severity, not
associated with swelling or changes on the skin overlying the joint. It was
neither related or affected by movement, nor associated or preceded by fever or
trauma.

He presented first
to the orthopedic department at the nearby regional hospital where he was
investigated for his right ankle problem. The tests done include plain x-ray
followed by a contrast-free axial and coronal CT of the right ankle. The films
showed multiple lytic changes with sclerotic margins involving the distal
metaphysis and epiphysis of the tibia and fibula. The report described presence
of bone cyst and suggested infiltrative bone pathology (fig.1and 2).

Fig.1: X-ray Rt. Ankle

Fig.2:CT. Rt. Ankle

Afterwards a
radio-isotope bone scan and bone biopsy were requested. Three phase bone scan
was done with 333 MBq of Tc-99m MDP and showed abnormal increased uptake of
radioactivity in the blood vessels around the joints and delayed images of both
feet suggestive of reflex sympathetic osteodystrophy.Also focal increased uptake was noted in both
8th ribs and the right 6th rib posteriorly (Fig 3 and 4).

The radiologist, in
his report, attributed the focal lesions to trauma rather than infection, but
he commented that metabolic bone diseases like osteomalacia and
hyperparathyroidism needs to be excluded. At that point, the
surgeon decided to operate on his right ankle. The bone cyst was excised and
sent for histopathology. The lab report read benign bone
degeneration with no evidence of malignancy or chronic inflammation.

Fig 3.

Fig 4.

Fig. 3 & 4: Three phase bone
scan with 333 MDPq of Tc-99m MDP.

After the surgical operation the patient
confined himself to bed for two days then he started to walk with support for
ten days with difficulty in standing from sitting position. Thereafter, his
condition became worse; he could not stand or walk or squat freely and he felt
significant pain in both hips and knees with each effort done to move his

lower limbs. However, his upper limbs were normal. He could
lift his arms over his head and his handgrip was preserved. This time he
consulted another orthopedic surgeon in a private clinic. He noted a positive
Gower sign on examination. The child was then investigated and the tests
results read as follows: Hb 13 g/dl, TWBC 9000 with normal differential,
platelets 320, and ESR 62 /mm/1st hour (westergren). Blood urea was
6.4 mmol/l (Ref. 2.5-7.5 mmol/l), plasma creatinine 53 mmol/l (Ref. 60-110
mmol/l), serum sodium 134 mmol/l, serum potassium 3.2 mmol/l, serum phosphorus
0.44 mmol/l (Ref. 0.9-1.5 mmol/l), and serum calcium 2.08 mmol/l (Ref. 2.1–2.55
mmol/l). Liver function tests and enzymes were normal apart from a high serum
level of ALP 1610 U/L (Ref. 65-260 U/L). A limited skeletal survey (only dorsal
spine, pelvis, upper femoral, and chest x-ray films) was performed and showed
decreased bone density. An EMG was done and suggested a myopathic pattern. The
surgeon advised a muscle biopsy, which was taken from the right quadriceps
femoris muscle. The section of the muscle biopsy showed thin muscle fibers with
aggregate nuclei, and without remarkable inflammation. The histological
features were reported as consistent with a diagnosis of muscular
dystrophy.The treating doctor diagnosed
the child as having Duchenne muscular dystrophy based upon the positive Gower
sign, the EMG result and the muscle biopsy report despite normal level of serum
Creatinine Kinase and absence of pseudohypertrophy of calf muscles. Parents
were told that no treatment is available for his problem and advised physiotherapy.
They were not convinced and sought medical advice at a neurology clinic.
Without doing any further investigations, the physician prescribed calcium
tablets and advised the patient to expose himself to sunlight. The condition
deteriorated with the calcium therapy, so the parents took the patient to a
pediatrician for the first time. The doctor examined the child, did few simple
tests and referred the child to our unit at Gaffar Ibn Auf Children Teaching
Hospital for further evaluation and management.

We interrogated the patient and noted the following history:

·Parents are first degree cousins; mother is hypertensive on
Atenolol and no history of hereditary diseases in the family.

·He is the shortest pupil since he joined the school at age 7 yrs
and has poor appetite and poor weight gain since he was thirteen years old.
Constipation for the last five months but no vomiting, abdominal pain or
distension.

·Polyuria and nocturia for the last four months but no enuresis,
dysuria or urgency.

·No past history of renal problems and he was not on regular
medication. He had malaria, which was treated by Artemether injections.

Examination showed no dysmorphic features and normal vital
signs. Both his weight and BMI were below the 3rd percentile for age and sex and
his height was -4 SD below the mean. The body’s upper over lower segment ratio
was 1.0, and arm span approximate his height. His pubertal development equals
Tanner stage 4. Hand, head, neck and ENT examination were normal. Physical eye
examination was normal. Slit lamp examination did not reveal Kayser-Fleischer
rings, cystine crystals or iritis. Fundoscopy revealed normal, fundi, no
maculopathy, retinitis pigmentosa or signs of retinopathy. Neurologic and
musculoskeletal examination found symmetrical muscle wasting more in the lower
limbs than the upper limbs, and affecting the proximal muscles more than the
distal muscles Muscle weakness was evident and Gower sign was positive. The
power in the small muscles of both hands and forearms was normal but grade 4 in
the pectorals, supraspinatus and the deltoid muscles on both sides of the body.
A mild kyphosis in his thoracic spine was also noted. Power in the muscles of
the toes and ankles was normal bilaterally, but grade 2 in the extensors &
flexors of both knees and grade 2 in the extensors, flexors, adductors and
abductors of the hip bilaterally. There was pain while actively moving the hips
and knees bilaterally. No joints stiffness, swelling, tenderness, deformity or
skin changes (apart of two scars of operation of what assumed to be bone cyst
in his right ankle and scar of muscle biopsy in his right thigh). No bowing of
legs, pseudo-hypertrophy of calves muscles, genu varum or coax vara.

The x-ray film of the left wrist showed decreased bone
density with fraying in the distal ends of the ulna and the radius and bone age
between 12 and 13 years. The thoracic spine x-ray film showed also decreased
bone density with increased anterioposterior curvature (fig. 5 and 6).

Abdominal sonography showed small kidneys 7.5 cm each with
poor medullo-cortical differentiations indicating chronic renal paranchymal
disease. There were no obstructive changes, calculi, cyst or nephrocalcinosis.
Renal biopsy was taken and showed no evidence of glomerular, tubular or
interstitial lesions.

Based on the history, the clinical examination, the
biochemical and the radiological features; we made a diagnosis of
hypophosphatemia secondary to proximal renal tubular acidosis, which is due to
Fanconi syndrome.

Fig 5. X- ray Lt.
Wrist .

Fig 6. X- ray
thoracic spine, lateral view

We prescribed the following medications: sodium bicarbonate
500 mg 6 hourly, potassium syrup 20 ml 6 hourly, phosphate tablet 500 mg 6
hourly, and alphacalcidol tablet 1 microgram OD. Physiotherapy was to be
initiated when bone lesions healed. One month after starting therapy, the
biochemical abnormalities returned to normal including the plasma phosphorus
level and metabolic acidosis. The patient’s overall quality of life improved
substantially; he was able to stand and walk without problems and he returned
to school after the long sick-leave.

Pitfalls of Diagnosis:

This patient
presented with difficulty in standing from sitting position, which suggests
proximal muscle weakness, together with bone pain in his lower limbs. However,
the attending doctor, an orthopedic surgeon, ignored the muscle weakness and
concentrated on the pain around the right ankle joint. He ordered bone x-ray
film, bone CT, and radio-isotope bone scans. The bone scan report was
suggestive of reflex sympathetic osteodystrophy and advised exclusion of
metabolic bone diseases. The doctor in charge ignored that report too and with
full trust in the radiological report, which claimed presence of bone cyst and
infiltrative bone pathology, he proceeded to surgical exploration and open bone
biopsy that proved to be normal. We showed the x-ray films to two experienced
radiologist in Khartoum and both reported (independently) that there was marked
decreased in the bone density and what assumed to be bone cysts in the distal
part of the tibia and fibula, was just haziness and irregularity at the zone of
ossification center of these bones, which is a known feature of early rickets.

In his second consultation, the patient was investigated
again by an orthopedic surgeon. The lab investigations showed marked
hypophosphatemia, hypokalemia, high alkaline phosphatase, and the skeletal
survey reported markedly decreased bone density. Nevertheless, a muscle biopsy was
taken and diagnosis of Duchenne muscular dystrophy made based mainly on EMG and
the muscle biopsy report. This diagnosis was not farfetched, because the
patient is a male and has history of progressive proximal muscle weakness with
positive Gower sign. What makes it unlikely were the negative family history
and absence of characteristic features of DMD (pseudohypertrophy of calves
muscles, macroglossia, cardiopulmonary involvement, and absent deep tendon
reflexes in the upper extremities and patella). Also the patient has features
that can’t be explained by DMD (polyuria & polydipsia, short stature and
the biochemical abnormality).In
addition, the histological features described in the biopsy report don’t support
the diagnosis of DMD, which is characterized by variations in muscle fiber
sizes with focal areas of degenerating & regenerating fibers.

In his third consultation, the patient was reviewed by a
neurologist who prescribed calcium and advised exposure to sunlight. The
contrast between the surgeon & the physician approach is clear here. By
reviewing the previous lab tests, the physician made the correct diagnosis of
rickets, but he failed to recognize its type or course; simply because he
didn’t do further tests. This mistake was avoided by the pediatrician who asked
for urinalysis, which revealed the glucosuria and the proteinuria.

When we evaluated
the patient, we noted the relevant history and physical signs and did thorough
investigations. We documented the metabolic acidosis, the hypokalemia and
hypophosphatemia, aminoaciduria and glucosuria with normal blood glucose
concentration and did a renal biopsy. We made the diagnosis of hypophosphatemic
rickets secondary to Fanconi syndrome and prescribed treatment, but that is not
the end of the road. Fanconi syndrome has many causes (table 1), and further
tests are needed to determine the exact type.

Table 1: Causes of Fanconi Syndrome

Category

Disease

Sporadic

Idiopathic

Genetic

Cystinosis

Lowe syndrome

Galactosemia/ Tyrosinemia

Hereditary fructose intolerance

Wilson disease

Dent disease

Fanconi-Bickel syndrome

Mitochondrial disease

Acquired

Heavy metal poisoning

Sodium Valproate

Gentamycin

Outdated Tetracycline

Cyclosporine

Ifosfamide

Vitamin D deficiency

This is important
for genetic counseling and for academic reasons, but from management point of
view all types are treated the same way.

Discussion:

The genetic and
hereditary causes of Fanconi syndrome are illustrated in Table 1. The commonest
inherited cause is Cystinosis, a systemic disease caused by a defect in the
metabolism of the aminoacid cystine 12-15. It is characterized by
accumulation of cystine crystals in many organs notably the kidneys and the
eyes. Patients usually present early, have fair skin and liver involvement.
Slit lamp examination of the eye and renal biopsy confirm the diagnosis. Both
were negative in our patient. The clinical findings together with the negative
family history confidently exclude cystinosis and the other hereditary
conditions (galactosemia, tyrosinemia, Lowe syndrome, Fanconi-Bickel syndrome,
Wilson disease and Dent disease) 16-19 as possible causes of Fanconi
syndrome in our patient. Although the idiopathic sporadic type of Fanconi
syndrome is rare and occurs mainly in Caucasians, it remains the most likely
cause of the condition in our patient. It has been reported before in blacks,
Hispanics, and people of Middle Eastern descent 20-21.

The acquired causes
of Fanconi syndrome are also shown in Table 1 above. It includes heavy metal
poisoning, drug toxicity and vitamin D deficiency 22. Of note is the
association between the commonly used anti-convulsant medication, Sodium
Valproate, and renal tubular acidosis 23-26. Another relatively new
drug, Ifosfamide, used in the treatment of Wilm’s tumour and some other solid
tumors in children is emerging as a potent induced of renal tubular acidosis
27-28.
All the known secondary causes of Fanconi syndrome were excluded in our
patient. Serum levels of vitamin D metabolites (25 hydroxycalciferol and 1, 25
dihydroxycholecalciferol) were normal and there was no history of heavy metals
or drugs ingestion. The only medicine the patient received was Artemether
injections for falciparum malaria two months before his current illness.
Artemether is a herbal-derived Chinese medicine not known to cause secondary
Fanconi syndrome. However, nephropathy has been reported following ingestion of
another herbal Chinese medicine, which was used to treat obesity in a woman
from Belgium 29. Also a popular Chinese herbal remedy containing
Arsitolochic acid, which is used to treat muscular and body aches in China,
Korea and Japan, has been identified to cause revisable transient Fanconi
syndrome 30. The pharmaco-kinetic studies on Artemether compounds
proved that sodium Artesunate inhibits sodium chloride transport in the thick
ascending limb of the loop of Henle and therefore has a diuretic and
natriuretic effect. But no evidence to date that Artemether causes proximal
renal tubular acidosis.

Conclusion:

The case highlights
the relationship between hypophosphatemia and proximal myopathy. It also
emphasizes the importance of urinalysis and measurement of bone minerals in all
patients with unusual, persistent musculoskeletal symptoms. The association of
Artemether and Fanconi needs further exploration.

Acknowledgments

We are very
grateful to Dr. Mohamed Babiker Abdulrahim, Assistant professor of Child
Health, university of Khartoum & consultant pediatric nephrologist at Soba
university hospital (SUH) who did the renal biopsy. We also thank the staff of
the labs at SUH & Elneileen Medical Centre for doing some of the tests.

27.
Church DN,
Hassan AB,
Harper SJ et al.Osteomalacia as a late metabolic complication of Ifosfamide chemotherapy
in young adults: illustrative cases and review of the literature.
Sarcoma 2007; 27: 91586.